Synthesis of omecamtiv mecarbil
Provided herein is a synthesis for omecamtiv mecarbil dihydrochloride hydrate and various intermediates.
1. A process for synthesizing phenyl (6-methylpyridin-3-yl) carbamate
comprising admixing 5-amino-2-methylpyridine
and phenyl chloroformate in acetonitrile to form PCAR, wherein the admixing is performed in the absence of N-methyl pyrrolidinone (NMP) and wherein purity of the APYR is ≥99 LC area %.
2. The process of claim 1 , wherein the admixing is performed at a temperature of 15 to 30° C. for 1 to 15 hours.
3. The process of claim 1 , wherein the PCAR is formed as a hydrochloride salt.
4. The process of claim 1 , further comprising preparing APYR by a process comprising:
(i) hydrogenating 2-methyl-5-nitropyridine
in the presence of a palladium catalyst to form crude APYR; and
(ii) crystallizing APYR from the crude APYR in isopropyl acetate and heptane.
5. The process of claim 4 , further comprising, prior to step (i), washing NPYR in isopropyl acetate with aqueous sodium hydroxide, followed by admixing the washed NPYR in isopropyl acetate with charcoal.
6. The process of claim 1 , further comprising, prior to admixing APYR and phenyl chloroformate, purifying APYR by a process comprising:
(i) washing an isopropyl acetate solution of crude APYR, wherein the crude APYR comprises up to 10 wt % APYR hydrochloride, with aqueous sodium hydroxide, and admixing the washed APYR with charcoal to form an APYR solution after filtration; and
(ii) crystallizing APYR from the APYR solution of step (i) from isopropyl acetate and heptane.
7. The process of claim 1 , further comprising crystallizing PCAR.